A classical method of producing a vaccine has been to produce a pure culture of a virus or bacterium and then inactivate the pathogen by using formalin, betapropiolactone, UV light or heat treatment. This methodology has been used successfully to produce vaccines against hepatitis A and B viruses, rabies virus, polio virus, pertussis, and bacterial toxins such as those from tetanus and diphtheria.
Initial attempts to produce an inactivated HIV vaccine have failed, largely due to the nature of the virus, which grows poorly and mutates rapidly. In addition, the trimeric viral spike is expressed at low densities on the native virus, thereby reducing its ability to elicit an immune response. To further complicate matters, the envelope (Env) protein, gp120, is shed from the virus in an apparently non-native form that elicits non-neutralizing antibodies.
Recently, a number of new broadly neutralizing antibodies have been discovered that have lead to the discovery of 3 sites of vulnerability on the viral spike protein (Env). These sites include the CD4 binding site, the V1/V2 quaternary epitopes (QNE), and a new glycan epitope. These sites are all discontinuous epitopes that are dependent on the conformation of the Env protein. The native Env protein consists of a trimer of gp120 proteins noncovalently attached to a trimer of gp41 peptides, and several of the new bNAbs preferentially or exclusively recognize Env trimers over gp120 monomers.
It has been difficult to produce reasonable quantities of virus envelope glycoprotein trimer in native and soluble form for use as vaccines. In addition, it has been exceedingly difficult to produce formulations of vaccines that contain native trimeric HIV Env such a way that these trimers are displayed in multimeric form such as to stimulate the immune system. Thus, Applicants' approach has been to produce virus glycoprotein, notably Env, on the surface of a heterologous virus, namely, vesicular stomatitis virus (VSV). Applicants have succeeded in replacing the native VSV G protein (which is the major surface protein on the virus that mediates attachment to cells) with HIV Env and rescuing replicating chimeric viruses. These VSV-Env chimeras express functional HIV Env that requires CD4 and CCR5 co-receptors for propagation. Thus, there is selective pressure for maintaining a significant level of functional Env of the surface of the virus. Applicants have shown that VSV chimeras expressing SIV Env can prime non-human primates (NHPs) for elicitation of antibody responses to Env, and Applicants' is to produce a replicating VSV vector to deliver HIV proteins for the induction of cell mediated immunity and neutralizing antibody responses.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.